EP0322391A1 - Nouveaux dérivés de la phénylalkylamine - Google Patents
Nouveaux dérivés de la phénylalkylamine Download PDFInfo
- Publication number
- EP0322391A1 EP0322391A1 EP88850429A EP88850429A EP0322391A1 EP 0322391 A1 EP0322391 A1 EP 0322391A1 EP 88850429 A EP88850429 A EP 88850429A EP 88850429 A EP88850429 A EP 88850429A EP 0322391 A1 EP0322391 A1 EP 0322391A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- hydrogen
- process according
- defined above
- prepared
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229940085239 selective calcium channel blockers with direct cardiac effects phenylalkylamine derivative Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 104
- 238000000034 method Methods 0.000 claims abstract description 80
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 40
- 239000001257 hydrogen Substances 0.000 claims abstract description 40
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 25
- 239000000203 mixture Substances 0.000 claims abstract description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 13
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 150000002367 halogens Chemical class 0.000 claims abstract description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 6
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 claims abstract description 3
- 230000003340 mental effect Effects 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 125000001424 substituent group Chemical group 0.000 claims abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- 230000002829 reductive effect Effects 0.000 claims description 10
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 230000009783 cholinergic response Effects 0.000 claims description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims description 6
- 230000003389 potentiating effect Effects 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 101100165225 Arabidopsis thaliana BETA-OHASE 2 gene Proteins 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 230000001747 exhibiting effect Effects 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 46
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- 239000000243 solution Substances 0.000 description 21
- -1 alaproclate Chemical class 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 206010044565 Tremor Diseases 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
- 239000013543 active substance Substances 0.000 description 9
- VZXWTKMWTTVISQ-UHFFFAOYSA-N 5-amino-1-(4-fluorophenyl)-2,2-dimethylheptan-3-one Chemical compound CCC(N)CC(=O)C(C)(C)CC1=CC=C(F)C=C1 VZXWTKMWTTVISQ-UHFFFAOYSA-N 0.000 description 7
- 239000001828 Gelatine Substances 0.000 description 7
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- 235000019322 gelatine Nutrition 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- 229960003225 alaproclate Drugs 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 0 C*C(CCCClC)*=C Chemical compound C*C(CCCClC)*=C 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 229960004132 diethyl ether Drugs 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
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- 239000012074 organic phase Substances 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- RSDOPYMFZBJHRL-UHFFFAOYSA-N Oxotremorine Chemical compound O=C1CCCN1CC#CCN1CCCC1 RSDOPYMFZBJHRL-UHFFFAOYSA-N 0.000 description 4
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- FZSPJBYOKQPKCD-VIFPVBQESA-N [1-(4-chlorophenyl)-2-methylpropan-2-yl] (2s)-2-aminopropanoate Chemical compound C[C@H](N)C(=O)OC(C)(C)CC1=CC=C(Cl)C=C1 FZSPJBYOKQPKCD-VIFPVBQESA-N 0.000 description 4
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- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 description 4
- 229920001592 potato starch Polymers 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical group [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- UMMMVYBZYNWLLN-UHFFFAOYSA-N 5-amino-1-(4-fluorophenyl)-2,2-dimethylheptan-3-ol;oxalic acid Chemical compound OC(=O)C(O)=O.CCC(N)CC(O)C(C)(C)CC1=CC=C(F)C=C1 UMMMVYBZYNWLLN-UHFFFAOYSA-N 0.000 description 3
- LSHMPBILLVWLQQ-UHFFFAOYSA-N 5-amino-1-(4-fluorophenyl)-2,2-dimethylheptan-3-one;oxalic acid Chemical compound OC(=O)C(O)=O.CCC(N)CC(=O)C(C)(C)CC1=CC=C(F)C=C1 LSHMPBILLVWLQQ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 206010027175 memory impairment Diseases 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 229920000945 Amylopectin Polymers 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 208000020401 Depressive disease Diseases 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 108090000862 Ion Channels Proteins 0.000 description 2
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- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 2
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- PVJWZVIXNIPJJG-UHFFFAOYSA-N 1-(4-fluorophenyl)-2,2-dimethylhept-4-en-3-one Chemical compound CCC=CC(=O)C(C)(C)CC1=CC=C(F)C=C1 PVJWZVIXNIPJJG-UHFFFAOYSA-N 0.000 description 1
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- JNNXWHNXLIPHDM-UHFFFAOYSA-N 5-amino-1-(4-fluorophenyl)-2,2,6-trimethylheptan-3-one;oxalic acid Chemical compound OC(=O)C(O)=O.CC(C)C(N)CC(=O)C(C)(C)CC1=CC=C(F)C=C1 JNNXWHNXLIPHDM-UHFFFAOYSA-N 0.000 description 1
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- JAILHURJJSCJRU-UHFFFAOYSA-N 5-amino-1-(4-fluorophenyl)-2,2-dimethyldecan-3-ol;oxalic acid Chemical compound OC(=O)C(O)=O.CCCCCC(N)CC(O)C(C)(C)CC1=CC=C(F)C=C1 JAILHURJJSCJRU-UHFFFAOYSA-N 0.000 description 1
- IPQIRQWQTVFAFW-UHFFFAOYSA-N 5-amino-1-(4-fluorophenyl)-2,2-dimethylhept-6-yn-3-one Chemical compound C#CC(N)CC(=O)C(C)(C)CC1=CC=C(F)C=C1 IPQIRQWQTVFAFW-UHFFFAOYSA-N 0.000 description 1
- FXSJQGVXYRJTNN-UHFFFAOYSA-N 5-amino-1-(4-fluorophenyl)-2,2-dimethylhept-6-yn-3-one;oxalic acid Chemical compound OC(=O)C(O)=O.C#CC(N)CC(=O)C(C)(C)CC1=CC=C(F)C=C1 FXSJQGVXYRJTNN-UHFFFAOYSA-N 0.000 description 1
- SCXASHYVIWRGGU-UHFFFAOYSA-N 7-(4-fluorophenyl)-5-hydroxy-6,6-dimethylheptan-3-one Chemical compound CCC(=O)CC(O)C(C)(C)CC1=CC=C(F)C=C1 SCXASHYVIWRGGU-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- 244000165918 Eucalyptus papuana Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229920004011 Macrolon® Polymers 0.000 description 1
- 238000000585 Mann–Whitney U test Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000006242 amine protecting group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- ZUDYPQRUOYEARG-UHFFFAOYSA-L barium(2+);dihydroxide;octahydrate Chemical compound O.O.O.O.O.O.O.O.[OH-].[OH-].[Ba+2] ZUDYPQRUOYEARG-UHFFFAOYSA-L 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- 208000025307 bipolar depression Diseases 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 201000003104 endogenous depression Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 210000002196 fr. b Anatomy 0.000 description 1
- 210000003918 fraction a Anatomy 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000010575 fractional recrystallization Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000007857 hydrazones Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000000472 muscarinic agonist Substances 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002923 oximes Chemical group 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 238000012306 spectroscopic technique Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
Definitions
- the object of the present invention is to provide novel compounds and therapeutically acceptable salts thereof with a potentiating effect on cholinergic responses.
- This invention also relates to processes for the preparation of the new compounds as well as to the pharmacological use of the new compounds and to pharmaceutical preparations containing such compounds.
- n 0 or 1
- Z is CO or CH(OH)
- R1 and R2 are equal or different and, when equal, hydrogen, methyl, ethyl or propyl and, when different, R1 is hydrogen and R2 is methyl, ethyl, propyl or isopropyl
- X and Y represent hydrogen, halogen, CF3, CN or an alkyl group, straight or branched having 1-3 carbon atoms, in the ortho, meta or para position provided that when X is in the ortho position and other than hydrogen then Y is other than hydrogen, and when Y is in the ortho position and other than hydrogen then X is other than hydrogen
- R represents a straight or branched saturated or unsaturated 1-6 carbon alkyl group, a 3-6 carbon cycloalkyl group, a phenyl group, which may be unsubstituted or may carry a ring substituent X1, X1 preferably being
- R is, when alkyl, preferably saturated straight or branched having 1-3 carbon atoms in the chain.
- R has, when cycloalkyl, preferably 5-6 carbon atoms in the ring.
- X, Y and X1 are preferably in the meta and/or para positions.
- Halogen X, Y and X1 is preferably bromo, chloro or fluoro in the meta and/or para positions and in particular in the para position when being the monosubstituent. Most preferred is para fluoro.
- X and/or Y is CF3 it is preferably in the meta position when being the monosubstituent, and in particular when R is a saturated alkyl group straight or branched having 1-3 carbon atoms in the chain.
- X and/or Y is CN it is preferably in the para position when being the monosubstituent, and in particular when R is a saturated alkyl group straight or branched having 1-3 carbon atoms in the chain.
- X and/or Y is alkyl it is preferably methyl in the para position when being the monosubstituent, and in particular when R is a saturated alkyl group straight or branched having 1-3 carbon atoms in the chain.
- the invention relates to new compounds of the general formula Ia, wherein Z is CO or CH(OH), X is halogen and R is a straight or branched alkyl group having 1-5 carbon atoms in the chain in racemic or optically active form, and when Z is CH(OH) also mixtures of diastereomers or the pure diastereomers, with the proviso that the racemate of the compound, wherein X is Cl, Z is CO and R is methyl is excluded; or pharmaceutically acceptable salts thereof.
- halogen is preferably chloro or fluoro and R is preferably an ethyl or isopropyl group.
- the compounds of the invention potentiate transmittor responses, probably by the modulation of ion-channels coupled to various neurotransmittor receptors. These effects makes it possible to use the compounds in the treatment of mental disturbances e.g. psychosis, schizophrenia, schizoaffective conditions, anxiety, unipolar and bipolar depression as well as in the treatment of minimal memory impairment (MMI) and of senile dementia of the Alzheimer type (SDAT).
- MMI minimal memory impairment
- SDAT senile dementia of the Alzheimer type
- certain compounds have a potentiating effect on central cholinergic responses. This potentiation is probably mediated by effects on ion channels, most likely of the potassium type. The latter two disturbances, MMI and SDAT, are believed to be associated with cholinergic dysfunction.
- the reducing agent is preferably sodium cyanoborohydride, sodium borohydride, or hydrogen in the presence of a catalyst e.g. Pd/C, Pt or Raney Ni. It is especially preferred to perform the reaction in methanol with sodium cyanoborohydride as reducing agent.
- the reducing agent is an appropriate reagent preferably chosen from the following: Sodium in liquid ammonia or lithium in an amine solution in the presence of an alcohol, or hydrogen in the presence of a catalyst,or lithium aluminium hydride or sodium borohydride in the presence of a Lewis acid. Most preferred is sodium in liquid ammonia in the presence of t-butanol for the preparation of compound I when Z is CO, and lithium aluminium hydride for the preparation of compound I when Z is CH(OH).
- the group Y1 in the compound V may be chosen from easily cleaved, chiral or nonchiral amides, carbamates, imines, benzylic amines or other suitable amine protecting groups. Such groups can be trifluoroacetamide, formamide, t-butylcarbamate, N-benzylamine, (S) or (R)-phenethylamine, or chiral Schiff bases such as (+) or (-)-2-hydroxypinanyl-3-indeneamines.
- Y1 can be groups such as nitro, azido, oxime, hydrazone or imine, which can be transformed to NH2 by known reductive processes.
- Y1 can be NR1R2 when R1 and/or R2 is hydrogen, which can be alkylated by known processes in a stepwise or direct manner.
- the compounds of the formula II can be isolated as such and subsequently converted to a compound of the formula I or the compounds of the formula II can be generated in situ and converted to a compound of the formula I without isolation.
- the group R may be an unsaturated alkyl or a suitable protected alkyn.
- the compounds of the formula I will normally be administered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or a pharmaceutically acceptable non-toxic, acid addition salt, e.g. the hydrochloride, hydrobromide, lactate, acetate, phosphate, sulphate, sulphamate, citrate, tartrate, oxalate and the like in association with a pharmaceutically acceptable dosage form.
- the dosage form may be a solid, semisolid or liquid preparation.
- the active substance will constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by weight for preparations intended for injection and between 0.2 and 50% by weight for preparations suitable for oral administration.
- the selected compound may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, e.g.
- the tablet can be coated with a polymer known to the man in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents or in water. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compounds.
- the active substance may be admixed with e.g. a vegetable oil or polyethylene glycol.
- Hard gelatine capsules may contain granules of the active substance using either the above mentioned excipients for tablets e.g. lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine. Also liquids or semisolids of the drug can be filled into hard gelatine capsules.
- Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.
- Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing from about 0.2 % to about 20 % by weight of the active substance herein described, the balance being sugar and mixture of ethanol, water, glycerol, and propylene glycol.
- Such liquid preparations may contain colouring agents, flavouring agents, saccarine and carboxymethylcellulose as a thickening agent or other excipients known to the man in the art.
- Solutions for parenteral applications can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from about 0.5 % to about 10 % by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.
- Suitable daily doses of the compounds of the invention in therapeutical treatment of humans are 100 to 500 mg at peroral administration and 20 to 100 mg at parenteral administration.
- the compounds according to the invention are characterized by standard spectroscopic techniques, e.g. 1H NMR and 13C NMR. Data are given in the following Tables 1 and 2. All data except for Example 9 are related to the respective base. For Example 9 the salt has been used.
- compositions 1 000 tablets can be made, containing 50 mg and 100 mg of active substance, respectively. If desired, the obtained tablets can be film coated with e.g. methyl cellulose in an organic solvent or using water.
- Example of solution for intravenous or intramuscular injection Compound according to Example 1 60 g Water for injection ad 1000 ml
- the active compound shall be dissolved in water to a final volume of 1000 ml and the solution filtered through a sterile 0.22 ⁇ m filter and aseptically dispensed into 1 ml sterile ampoules, which then are sealed.
- mice Male rats (Sprague Dawley Alab Laboratorietjänst AB, Sollentuna, Sweden) weighing 150-180 g, 35-40 days of age, were used. The animals were allowed free access to food (R3, Ewos AB, Södertälje, Sweden) and water until the start of the experiments. The test compounds were injected intraperitoneally (i.p.) 30 minutes before injection of the muscarine agonist oxotremorine (OTM) into the neck (s.c.). Tremor intensity was assessed visually for a 60 minutes period following the injection of OTMN in rat housed in Macrolon cages (25x25x30 cm) (three per cage). The threshold dose of OTMN for eliciting tremor in rat is about 200 ⁇ g/kg.
- OTMN oxotremorine
- the compounds of the general formula I potently potentiate the tremor inducing effect of oxotremorine, which indicates a facilitation of central cholinergic responses.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Steroid Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Jib Cranes (AREA)
- Superconductors And Manufacturing Methods Therefor (AREA)
- Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT88850429T ATE73993T1 (de) | 1987-12-21 | 1988-12-20 | Neue phenylalkylamin-derivate. |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE8705089A SE8705089D0 (sv) | 1987-12-21 | 1987-12-21 | New compounds |
SE8705089 | 1987-12-21 | ||
SE8804277 | 1988-11-25 | ||
SE8804277 | 1988-11-25 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0322391A1 true EP0322391A1 (fr) | 1989-06-28 |
EP0322391B1 EP0322391B1 (fr) | 1992-03-25 |
Family
ID=26660072
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP88850429A Expired - Lifetime EP0322391B1 (fr) | 1987-12-21 | 1988-12-20 | Nouveaux dérivés de la phénylalkylamine |
Country Status (25)
Country | Link |
---|---|
EP (1) | EP0322391B1 (fr) |
JP (1) | JPH02240A (fr) |
KR (1) | KR890009848A (fr) |
CN (1) | CN1023478C (fr) |
AT (1) | ATE73993T1 (fr) |
AU (1) | AU611978B2 (fr) |
DE (1) | DE3869583D1 (fr) |
DK (1) | DK713088A (fr) |
EG (1) | EG18654A (fr) |
ES (1) | ES2033013T3 (fr) |
FI (1) | FI885905A (fr) |
GR (1) | GR3004617T3 (fr) |
HU (1) | HU204765B (fr) |
IE (1) | IE61133B1 (fr) |
IL (1) | IL88641A (fr) |
IS (1) | IS1556B (fr) |
LV (1) | LV10244A (fr) |
MY (1) | MY104117A (fr) |
NO (1) | NO169837C (fr) |
NZ (1) | NZ227299A (fr) |
PL (3) | PL161564B1 (fr) |
PT (1) | PT89272B (fr) |
RU (1) | RU1836331C (fr) |
SU (1) | SU1750418A3 (fr) |
YU (3) | YU231888A (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992014726A1 (fr) * | 1991-02-23 | 1992-09-03 | Bayer Aktiengesellschaft | Pyridylpyrimidines substituees, leur preparation et leur utilisation, ainsi que nouveaux intermediaires |
WO1995011224A1 (fr) * | 1993-10-22 | 1995-04-27 | Abbott Laboratories | Procedes de preparation d'un 2,5-diamino-3-hydroxyhexane substitue |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100769320B1 (ko) * | 2007-08-07 | 2007-10-24 | 태 봉 김 | 사격장 탄두회수장치 |
Citations (2)
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US4177291A (en) * | 1976-08-25 | 1979-12-04 | Astra Lakemedel Aktiebolag | Compounds having antidepressive activity |
US4469707A (en) * | 1983-04-29 | 1984-09-04 | Astra Lakemedel Aktiebolag | Method for treatment of senile dementia |
-
1988
- 1988-12-06 NO NO885412A patent/NO169837C/no unknown
- 1988-12-09 MY MYPI88001426A patent/MY104117A/en unknown
- 1988-12-09 IL IL88641A patent/IL88641A/xx not_active IP Right Cessation
- 1988-12-12 AU AU26775/88A patent/AU611978B2/en not_active Ceased
- 1988-12-13 NZ NZ227299A patent/NZ227299A/en unknown
- 1988-12-19 IE IE378588A patent/IE61133B1/en not_active IP Right Cessation
- 1988-12-20 ES ES198888850429T patent/ES2033013T3/es not_active Expired - Lifetime
- 1988-12-20 DE DE8888850429T patent/DE3869583D1/de not_active Expired - Fee Related
- 1988-12-20 PL PL88281863A patent/PL161564B1/pl unknown
- 1988-12-20 IS IS3422A patent/IS1556B/is unknown
- 1988-12-20 JP JP63319705A patent/JPH02240A/ja active Pending
- 1988-12-20 PL PL88281864A patent/PL161565B1/pl unknown
- 1988-12-20 PL PL1988276562A patent/PL156473B1/pl unknown
- 1988-12-20 AT AT88850429T patent/ATE73993T1/de not_active IP Right Cessation
- 1988-12-20 PT PT89272A patent/PT89272B/pt active IP Right Grant
- 1988-12-20 KR KR1019880017066A patent/KR890009848A/ko not_active Application Discontinuation
- 1988-12-20 EG EG646/88A patent/EG18654A/xx active
- 1988-12-20 HU HU886513A patent/HU204765B/hu not_active IP Right Cessation
- 1988-12-20 EP EP88850429A patent/EP0322391B1/fr not_active Expired - Lifetime
- 1988-12-21 CN CN88108785A patent/CN1023478C/zh not_active Expired - Fee Related
- 1988-12-21 DK DK713088A patent/DK713088A/da not_active Application Discontinuation
- 1988-12-21 FI FI885905A patent/FI885905A/fi not_active Application Discontinuation
- 1988-12-21 YU YU02318/88A patent/YU231888A/xx unknown
-
1989
- 1989-12-08 RU SU894742608A patent/RU1836331C/ru active
- 1989-12-11 SU SU894742613A patent/SU1750418A3/ru active
-
1990
- 1990-03-28 YU YU00605/90A patent/YU60590A/xx unknown
- 1990-03-28 YU YU00604/90A patent/YU60490A/xx unknown
-
1992
- 1992-05-18 GR GR920400941T patent/GR3004617T3/el unknown
-
1993
- 1993-06-30 LV LV930855A patent/LV10244A/xx unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US4177291A (en) * | 1976-08-25 | 1979-12-04 | Astra Lakemedel Aktiebolag | Compounds having antidepressive activity |
US4469707A (en) * | 1983-04-29 | 1984-09-04 | Astra Lakemedel Aktiebolag | Method for treatment of senile dementia |
Non-Patent Citations (1)
Title |
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Eur. J. Med. Chem.-Chimica Therapeutica November-December 1981-16, No 6, pages 495-501, U.H. LINDBERG et al: "Inhibitors of Neuronal Monoamine Uptake III. Synthesis and Pharmacologic Screening of Alaproclate Analogues", * see the whole document * * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992014726A1 (fr) * | 1991-02-23 | 1992-09-03 | Bayer Aktiengesellschaft | Pyridylpyrimidines substituees, leur preparation et leur utilisation, ainsi que nouveaux intermediaires |
US5416088A (en) * | 1991-02-23 | 1995-05-16 | Bayer Aktiengesellschaft | Substituted pyridylpyrimidines, their preparation and their use |
US5502233A (en) * | 1991-02-23 | 1996-03-26 | Bayer Aktiengesellschaft | Enamine intermediates for the preparation of substituted pyridylpyrimidines |
WO1995011224A1 (fr) * | 1993-10-22 | 1995-04-27 | Abbott Laboratories | Procedes de preparation d'un 2,5-diamino-3-hydroxyhexane substitue |
US5491253A (en) * | 1993-10-22 | 1996-02-13 | Abbott Laboratories | Process for the preparation of a substituted 2,5-diamino-3-hydroxyhexane |
US5508409A (en) * | 1993-10-22 | 1996-04-16 | Abbott Laboratories | Process for the preparation of a substituted 2.5-diamino-3-hydroxyhexane |
US5616776A (en) * | 1993-10-22 | 1997-04-01 | Abbott Laboratories | Process for the preparation of a substituted 2.5-diamono-3-hydroxy-hexane |
EP0916646A2 (fr) * | 1993-10-22 | 1999-05-19 | Abbott Laboratories | Préparation d'une 2,5-diamino-3-hydroxyhexane substituée |
EP0916646A3 (fr) * | 1993-10-22 | 1999-08-18 | Abbott Laboratories | Préparation d'une 2,5-diamino-3-hydroxyhexane substituée |
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